Bacterial vaginosis (BV) is one of the most common disorders in women of reproductive age. According to the US Centers for Disease Control and Prevention (CDC), risk factors for BV include douching and having new or multiple sex partners. BV is caused by an imbalance of naturally occurring bacterial microbiota and can be microbiologically characterized by replacement of the lactobacilli-predominant vaginal microbiota by potential pathogenic vaginal bacteria. The change from a healthy, H2O2 and lactic acid producing lactobacilli-dominated microbiota to a complex multispecies microbiota can occur relatively quickly and result in BV.
As discussed in e.g. EP0257007 (filed 1987)—it has been known for long time that Bacterial vaginosis (BV) is accompanied by a rise in pH (rise from normal/healthy pH of approximately 4 to a pH above 4.5) and a microbial dysbiosis in which the usually dominant Lactobacillus vaginal microbiota is overwhelmed by an overgrowth of predominantly anaerobic organisms.
EP2509610B1 (HSO Health Care, Vienna—filed Sep. 13, 2011 and published/granted in 2013) provides a summary of herein relevant background prior art.
As discussed in EP2509610B1—the healthy human vagina is dominated by a variety of Lactobacillus species, which play an essential role in protecting women from urogenital infection. Lactobacilli have the ability to adhere to vaginal epithelia, to inhibit the adhesion and growth of pathogens, deplete nutrients otherwise available to pathogens, and modulate the host immune response and microenvironment. Most importantly, Lactobacilli metabolize the glycogen contained in the cells of the vaginal vault, forming lactic acid as the final product. Thus, in a healthy vagina, pH-values of around 4.0 are reached, a level at which many pathogens cannot flourish.
When administrated to a woman in the form of a pharmaceutical composition (e.g. vaginal capsules for vaginal administration)—the protective effect of Lactobacilli against potential pathogens in the vagina is generated through the metabolic activity of the Lactobacilli. The bacteria consume glycogen and other sources of glucose and produce lactic acid. The low pH generated in this manner is harmful to the less desirable bacteria and fungi and thus protects the vaginal mucosa against infections.
Because vaginal infection is an important mechanism of disease responsible for preterm birth, maintaining the natural, healthy balance of the Lactobacillus microbiota in the vagina is particularly important during pregnancy. A deficiency in Lactobacilli can upset the microbial balance in the vagina, frequently resulting in the syndrome of bacterial vaginosis, which may be associated with a quantitative and qualitative shift from normally occurring Lactobacilli to a mixed microbiota dominated by anaerobic bacteria. According to the art, bacterial vaginosis may be characterized by a complete loss of Lactobacilli and a concomitant increase in Gram-variable and Gram-negative rods, primary among them Gardnerella vaginalis as well as Bacteroides, Prevotella, and Mobiluncus species. However, loss of vaginal Lactobacilli also leaves nonpregnant women susceptible to infection which may result in endometritis or even pelvic inflammatory disease.
During menopause, involution of the female genital tract occurs, reflecting possibly a built-in biologic life expectancy interrelated with the neurohypophyseal endocrine axis. The major universal change is vaginal atrophy. Vaginal dryness, burning, itching and dyspareunia are frequent complaints along with dysuria, urinary frequency and recurrent infections. The genitourinary atrophy following menopause is associated with a decline in estrogen secretion accompanied by depletion of Lactobacilli and increased colonization by pathogenic microorganisms associated with bacterial vaginosis and urinary tract infections. In post-menopausal women, vaginal estriol therapy reduces Escherichia coli colonization and increases the numbers of Lactobacilli, with the result that the incidence of recurrent urinary and genital tract infections drops significantly.
Several species of Lactobacillus have been described to populate the vagina to varying degrees. For some time the microbiota of healthy women of childbearing age was believed to be dominated by L. acidophilus and L. fermentum, followed by L. brevis, L. jensenii and L. casei. In another study on the vaginal Lactobacillus microbiota the authors found that the vaginal microbiota of most participants was dominated by a single Lactobacillus species, with the presence of other species showing wide individual variability. The most frequently occurring species were L. crispatus, L. gasseri, L. iners, and L. jensenii. In another study, the most commonly isolated Lactobacillus strains were L. jensenii, L. acidophilus, L. casei, and L. gasseri. In recent Austrian studies, the predominant Lactobacillus species identified by species-specific PCR, namely L. crispatus, L. gasseri, L. jensenii, and L. rhamnosus were used to generate DNA fingerprints. L. crispatus, L. gasseri, L. jensenii and L. rhamnosus can be regarded as the predominant species in the vagina.
To remedy deficiencies in the Lactobacillus microbiota (and hence, in the protective capability of the vaginal microbiota), the administration of vaginal suppositories containing Lactobacilli is the most common way of Lactobacilli substitution. Some authors believe that the topical use of Lactobacilli is a safe and promising treatment for the prevention of vaginosis and recurrent urinary tract infections.
While vaginal supplementation is a long-standing, widely accepted practice for Lactobacilli substitution, oral administration of a Lactobacillus preparation represents a new concept for the restitution of a normal vaginal microbiota. Relatively recent results indicate that the probiotic strains L. rhamnosus GR-1 (ATCC 55826) and L. reuteri RC-14 (ATCC 55845) can be taken orally on a daily basis for two months without any side effects. The consumption then resulted in a significant improvement of the vaginal microbiota in terms of increased Lactobacilli presence and decreased yeast and coliforms. While one group of authors discussed the beneficial effects in terms of an alteration in mucosal immunity or of probiotic bacteria ascending to the vagina from the rectal area, another group recently demonstrated, by species-specific PCR-amplification, that L. rhamnosus GR-1 and L. reuteri RC-14 can be delivered to the vaginal environment when administered orally.
In view of above discussed prior art—the invention as described in EP2509610B1 relates to a use of a combination of specific deposited strains of L. crispatus, L. rhamnosus, L. jensenii and/or L. gasseri for treatment of bacterial vaginosis (BV). In table 11 on page 15 is shown that e.g. deposited L. rhamnosus (DSM22560) has a relatively good capability to lower pH.